Numerous oxime ethers have been shown to have biological activity. See, e.g., U.S. Pat. Nos. 4,158,015; 5,354,883; 5,318,978; and 5,306,718; European published application EP 0 445 731 A1; and PCT published applications WO 93/08192; WO 94/13678; and WO 95/34562; and publications S. A. Matlin et al., "Resolution and Identification of Steroid Oxime Syn and Anti Isomers by HPLC, " J. LIQUID CHROMATOGRAPHY, 13 (17), pp. 3455-3463 (1990); and J. van Dijk et al., "Oxime Ether Derivatives, A New Class of Nonsteroidal Antiinflammatory Compounds," J. MED. CHEM., 20 (9), pp. 1199-1206 (1977), all these patents and publications incorporated herein by reference. For example, [R-(Z)]-1-azabicyclo[2.2.1]heptan-3-one, O-[3-(3-methoxyphenyl)-2-propynyl]oxime has been demonstrated to be a muscarinic agonist which is expected to be useful in treating cognitive disorders, including Senile Dementia Alzheimers Type (SDAT). Reference may be had to PCT/US95/05033 (WO 95/34562); U.S. Pat. No. 5,346,911; EP 0 445731 A1; U.S. Pat. No. 5,318,978; U.S. Pat. No. 5,306,718; and PCT/US92/08642 (WO 93/08192), these patents and/or published applications incorporated herein by reference. This and other oxime ethers may therefore prove to be powerful and valuable pharmaceuticals.
In order to be useful as a pharmaceutical on a commercial scale, and to facilitate testing for regulatory approval, a target compound must be capable of economical synthesis and isolation in high yield and purity. Oxime ethers, for example, are capable of existing in both Z and E forms. As is the case with many pharmaceutically active compounds, only one isomer displays the desired pharmacological activity. However, the synthesis of oxime ethers generally results in a mixture of both Z and E isomers. Conversion of Z and E isomers can be accomplished under suitable conditions for certain oximes, although the mechanisms of the conversions are not well known. The barrier to isomerization has been reported as large, J. AM. CHEM. SOC., 88, p. 2775 (1966).
Methods which have proven useful in oxime isomer conversions include photochemical conversion, A. Padwa et al., "Concentration Effects in the Photochemical Syn-Anti Isomerism of an Oxime Ether," J. ORG. CHEM., 39 2361-2366 (1974); A. C. Pratt et al., "Photochemistry of the Carbon-Nitrogen Double Bond. Part I. Carbon--Nitrogen v.s. Carbon--Carbon Double Bond Isomerization in the Photochemistry of .alpha., .beta.-Unsaturated Oxime Ethers: the Benzylideneacetone Oxime O-Methyl Ether System", J. CHEM. SOC., P1, 1691-1693 (1986); by thermal conversion, J. Bi.o slashed.rgo et al., "Conformational and Electronic Effects on Imine Stereochemistry", TET. LETT., 1747-1750 (1972); and acid catalysis, C. R. Hauser et al., "Syn-Anti Isomerism of p-Chlorobenzaldoxime with Boron Fluoride", J. ORG. CHEM., 20 1491-1495 (1955); J. MED. CHEM., op. cit. In addition, thermal conversion of syn to anti configurations of imines, oxime esters, and haloimines was reported by D. Y. Curtin et al., "Uncatalyzed syn-anti Isomerization of Imines, Oxime Ethers, and Haloimines", J. AM. CHEM. SOC., 88 pp. 2775-2786 (1966). The general solvent preference is an anhydrous organic solvent. Biochemical resolution of oxime ethers was reported by M. Murakata et al., "Lipase-catalyzed Kinetic Resolution of Phenylcyclohexanone Oxime Ethers" TETRAHEDRON:ASYMMETRY, 5 (10) pp. 2019-2024 (1994). However, each of these methods generally results in the preparation of enriched isomer mixtures still containing an unacceptably large amount of the undesired isomer. As these compounds differ only in the stereochemical configuration about the oxime nitrogen, their separation is problematic.
Final purification of Z isomer-enriched oxime ether mixtures thus far has required chromatographic techniques such as medium or high pressure liquid chromatography. However, such chromatographic methods, while suitable for laboratory or semi-preparative separations, are ill-suited for commercial preparation of multi-kilogram quantities. Without an efficient, cost-effective means of purification, even the most promising pharmaceuticals cannot be commercialized.
It would be desirable to provide a process by which oxime ethers can be synthesized and isolated as the Z isomer in substantial purity without the use of chromatographic techniques. It would be further desirable to provide a process whereby isomerization of the Z isomer to the E isomer may be achieved simply and inexpensively and the Z isomer isolated in high purity with minimal processing steps.